Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Abstract

A vaccine against congenital human cytomegalovirus (CMV) infection is a major public health priority. Congenital CMV causes substantial long-term morbidity, particularly sensorineural hearing loss (SNHL), in newborns, and the public health impact of this infection on maternal and child health is underrecognized. Although progress toward development of a vaccine has been limited by an incomplete understanding of the correlates of protective immunity for the fetus, knowledge about some of the key components of the maternal immune response necessary for preventing transplacental transmission is accumulating. Moreover, although there have been concerns raised about observations indicating that maternal seropositivity does not fully prevent recurrent maternal CMV infections during pregnancy, it is becoming increasing clear that preconception immunity does confer some measure of protection against both CMV transmission and CMV disease (if transmission occurs) in the newborn infant. Although the immunity to CMV conferred by both infection and vaccination is imperfect, there are encouraging data emerging from clinical trials demonstrating the immunogenicity and potential efficacy of candidate CMV vaccines. In the face of the knowledge that between 20,000 and 30,000 infants are born with congenital CMV in the United States every year, there is an urgent and compelling need to accelerate the pace of vaccine trials. In this minireview, we summarize the status of CMV vaccines in clinical trials and provide a perspective on what would be required for a CMV immunization program to become incorporated into clinical practice.

Impact of Maternal Immunity on Congenital Cytomegalovirus Birth Prevalence and Infant Outcomes: A Systematic Review

“…Approximately 85-90% of infants born with cCMV are asymptomatic, while only 10% of infants are symptomatic at birth [9,10]. Of those infants who demonstrate CMV-associated sequelae at birth, 40-60% will develop permanent sequelae including cerebral palsy, cognitive impairment, microcephaly and sensorineural hearing loss (SNHL) [7,10,11]. Those who are born asymptomatic are also at risk of developing sequelae; as 6-23% of asymptomatic infants eventually develop SNHL.…”

“…We also utilized a recent study that differentiated primary maternal infections from chronic infections in a highly seropositive population to calculate a placental transmission rate in women with pre-existing immunity compared to that of no pre-existing immunity. This work confirms a low cCMV birth prevalence in highly seropositive populations, indicates via a calculated placental transmission rate that the CMV placental transmission rate is lower in non-primary infection than that of primary infection, and reveals gaps in data for further research aiming to identify targets for vaccine development.Vaccines 2019, 7, 129 2 of 13 leading non-genetic cause of SNHL [9,11]. Furthermore, as many as 5% of infants without recognizable CMV-associated sequelae at birth may develop microcephaly or neurodevelopmental deficits within the first year of life [10].Placental transmission of CMV occurs in mothers with both prior natural immunity to CMV, termed 'non-primary CMV infection', and among seronegative mothers who contract CMV during pregnancy, termed 'primary infection' [2,5,12].…”

“…Vaccines 2019, 7, 129 2 of 13 leading non-genetic cause of SNHL [9,11]. Furthermore, as many as 5% of infants without recognizable CMV-associated sequelae at birth may develop microcephaly or neurodevelopmental deficits within the first year of life [10].…”

Techniques to Study Antigen-Specific B Cell Responses

“…Influenza also performs fusion through the stem region of the hemagglutinin protein, and the identification of B cells that target this relatively conserved site has spurred research on the development of a universal influenza vaccine (14)(15)(16). Like RSV, HIV, and influenza, the fusion proteins of EBV and CMV exist in a pre-fusion conformation, and stabilization in their pre-fusion states could greatly accelerate vaccine development against these pathogens (17)(18)(19). Rare memory B cells producing antibodies specific for the EBV fusion machinery have been isolated; these can neutralize both B cell and epithelial cell infection (20).…”

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

“…Unfortunately, CMV has proven to be a challenging target for vaccine development. To date, most CMV vaccine efforts focus on elicitation of antibodies against viral glycoproteins or generation of antiviral Tcell responses (Schleiss et al, 2017). Administration of a MF59-adjuvanted CMV glycoprotein B (gB) vaccine to CMV-seronegative adolescent girls induced strong gB-specific antibody responses and afforded 43% protective efficacy (Bernstein et al, 2016).…”